The Anatomy of Man

The Anatomy of Man

Pituitary and Hypothalamic Disorders


Pituitary and Hypothalamic Disorders
Physiology

Growth Hormone

is a 191-amino acid peptide. Secretion is stimulated by two hypothalamic  growth hormone-releasing hormones and inhibited by the hypothalamic tetradecapeptide somatostatin. GH binds to receptors in the liver and induces insulin-like growth factor 1, which mediates most of the growth-promoting effects of the growth hormone.
Prolactin has 198 amino acids. Its secretion is under inhibitory control by hypothalamic dopamine. TRH and vasoactive intestinal polypeptide (VIP) are prolactin-releasing factors. Prolactin levels increase during pregnancy, enhancing breast development. Postpartum prolactin stimulates milk production.
Evaluation of prolactin reserve: prolactin levels increase 3 to 5fold 15 to 30 minutes after TRH administration (200 µg i.v.)

Thyroid-stimulating hormone (TSH)
28,000 dalton glycoprotein hormone. TSH secretion is stimulated by the hypothalamic tripeptide TRH. Negative feedback inhibition of TSH secretion by peripheral thyroid hormones.

Adrenocorticotropic Hormone (ACTH)
A  39-amino acid peptide. Hypothalamic corticotropin-releasing hormone (CRH) stimulates ACTH secretion. Cortisol exerts a negative feedback effect on ACTH and CRH.

Gonadotropins (LH and FSH)
Hypothalamic GnRH regulates LH and FSH secretion. Gonadal steroids exert both positive and negative feedback effects on gonadotroph secretion. LH stimulates gonadal steroid secretion by testicular Leydig cells and by the ovarian follicles. In females, the ovulatory LH surge results in rupture of the follicle and then luteinization. In males, FSH stimulates Sertoli cell spermatogenesis, and in females, follicular development.


Pituitary adenomas
Clin: headache, visual loss (typically bitemporal hemianopia), syndromes of hypopituitary hormone hypersecretion and hyposecretion, and incidentally discovered sellar enlargement.

Hypothalamic dysfunction
In children and young adults, craniopharyngioma is the most frequent cause of hypothalamic dysfunction.
Clin: visual loss, symptoms of raised intracranial pressure {headache and vomiting), hypopituitarism including growth failure, and diabetes insipidus.
Hypothalamic disturbances: disorders of thirst (dehydration or polydipsia and polyuria), appetite (hyperphagia and obesity), temperature regulation, behaviour, and consciousness (somnolence and emotional lability).
Craniopharyngeoma is treated primarily with surgical resection and then radiotherapy.

Hypopituitarism
results from diminished secretion of one or more pituitary hormones. Pituitary insufficiency is usually a slow, insidious disorder.
 
Growth Hormone Deficiency
during infancy and childhood  growth retardation, short stature, and fasting hypoglycemia.
In adults: increased abdominal adiposity, reduced strength and exercise capacity, cold intolerance, impaired psycho-social well-being. Adult GH deficiency is usually accompanied by other symptoms of panhypopituitarism.
 
TSH deficiency
causes thyroid gland involution and hypofunction.
Clin: lethargy, constipation, cold intolerance, bradycardia, weight gain, dry skin, poor appetite, and delayed reflex relaxation time.
Dg: low TSH + low T4 and T3

Etiology of hypopituitarism
type of disorder                       
congenital                                    septo-optic dysplasia
                                                                        Prader-Willi syndrome
                                                                        Lawrence-Moon-Biedle syndrome
isolated anterior pituitary hormone or RF deficiency
tumors                                    pituitary
                                                                        secretory adenomas
                                                                        nonsecretory adenomas
                                                hypothalamic
                                                                        craniopharyngioma
                                                                        hamartoma
                                                                        pinealoma
                                                                        dermoid
                                                                        epidermoid
                                                                        glioma
                                                                        lymphoma
                                                                        meningioma
immunological                        autoimmune lymphocytic hypophysitis
infiltrative                                    hemochromatosis
                                                Langerhans cell histiocytosis
                                                sarcoidosis
                                                metastatic carcinoma
                                                amyloidosis
infectious                                    tuberculosis
                                                mycoses
                                                syphilis
physical trauma                        cranial trauma and hemorrhage
                                                ionizing radiation
                                                stalk section
                                                surgery
vascular            postpartum pituitary necrosis (Sheehan's syndrome)
                                                pituitary apoplexy
                                                carotid aneurysm

Gonadotropin deficiency
Central hypogonadism in childhood results in failure to enter normal puberty. Females have delayed breast development, scant pubic and axillary hair, and primary amenorrhea. In boys, the phallus and testes remain small, and body hair is sparse.
Sex steroids are required for closure of the epiphyses of the long bones.   Clin: tall adolescents with eunuchoid proportions. In adult women, hypogonadism presents as breast atrophy, loss of pubic and axillary hair, and secondary amenorrhea. Hypogonadal adult males develop testicular atrophy, decreased libido, impotence, and loss of body hair.

ADH (vasopressin) deficiency
occurs with posterior pituitary dysfunction and leads to DI with polyuria, polydipsia, and nocturia.

Dg of pituitary hormone deficiency
Quadruple Bolus Test for Anterior Pituitary Reserve
hypothalamic releasing hormone                        pituitary hormone
TRH 200 µg                                                                        TSH, prolactin
CRF 1 µg/kg                                                            ACTH
GHRH 1 µg/kg                                                            GH
gonadotropin RH 100  µg                                    FSH, LH

Th of panhypopituitarism           
replacement of thyroxine, glucocorticoids, and sex steroids. Children with short stature should receive GH replacement therapy. Testosterone therapy in males restores libido and potency, beard growth, and muscle strength.
Estrogen replacement therapy in females maintains secondary sex characteristics and prevents hot flashes. Human menopausal gonadotropins and human chorionic gonadotropin given i.m. or gonadotropin RH administered by infusion pumps may be given to induce ovulation.
In patients with combined TSH and ACTH deficiency, glucocorticoids should be replaced prior to thyroxine, as thyroxine may precipitate acute adrenal failure.

Empty Sella Syndrome
occurs when the arachnoid membranes herniate through an incompetent diaphragma sella and extend into the sella turcica, partially filling it with cerebrospinal fluid and compressing the pituitary gland. Primary empty sella syndrome is the most common cause of an enlarged sella turcica. This results from a congenital weakness in the diaphragma sella.
Secondary empty sella syndrome can occur following pituitary surgery or radiation therapy or in Sheehan's syndrome.  Empty sella syndrome is usually asymptomatic and detected incidentally on routine imaging of the head. Endocrine function is usually normal; partial hypopituitarism may be present.
Dg: MRI - fluid in sella turcica

Pituitary tumours
Prolactinomas are the most common secretory pituitary tumours.
Secretory pituitary tumours: signs and symptoms due to hypersecretion of  the particular pituitary trophic hormone.
GH adenomas:   acromegaly, prolactinomas:  amenorrhoea + galactorrhea in females and sexual dysfunction in males, ACTH-secreting adenomas:   Cushing disease.
Large pituitary adenomas (secretory or nonsecretory) can result in signs and symptoms due to pressure on surrounding structures. Headache is a frequent symptom. Extension of the tumour into the suprasellar space ®   compression of the optic chiasm  bitemporal hemianopia. Lateral extension into the cavernous sinus can result in ophthalmoplegia, diplopia, or ptosis due to dysfunction of the third, fourth, fifth, and sixth cranial nerves. Compression of surrounding normal pituitary tissue due to an enlarging tumor mass can cause hyposecretion of one or several pituitary trophic hormones.
Destructive pituitary lesions result in hormone loss in the following pattern: GH - LH/FSH - TSH - ACTH - prolactin.

Prolactinomas
Hyperprolactinemia in women:  hypogonadism ®  estrogen deficiency.  Gonadotropin levels are normal, and sex steroids are decreased. Prolactin inhibits pulsatility in gonadotropin secretion ®   anovulation. In hyperprolactinemic males, testosterone levels are usually suppressed.
Clin: in women, amenorrhea, galactorrhea, and infertility. Estrogen deficiency may cause osteopenia, vaginal dryness, hot flashes, and irritability. Prolactin stimulates adrenal androgen production ®  weight gain and hirsutism.
Males usually present with loss of libido and impotence due to hypogonadism.
Dg: basal serum prolactin level > 200 ng/ml; MRI.
Th: bromocriptine (a dopamine agonist) at a dosage of 2.5 to 15 mg/day orally in divided doses restores gonadal function and fertility in a majority of patients. Bromocriptine may cause tumour shrinkage. Surgery is indicated in patients with visual field abnormalities or neurologic symptoms. Trans-sphenoidal microsurgery is the procedure of choice.

Acromegaly and gigantism
In childhood, hypersecretion of GH leads to gigantism, in adults     acromegaly (local overgrowth of bone in the acral areas).
Clin: acral enlargement - widening of the hand and feet and coarsening of the facial features.  The mandible grows downward and forward   ® prognathism and widely spaced teeth. Ring, glove, and shoe size increase.
Dg: insulin-like growth factor-1 mediates the classical acral changes that occur with acromegaly. IGF-1 levels are elevated.
GH levels 2 hours after an oral glucose load of 100g. In healthy persons, GH levels are suppressed to < 2 ng/ml.
MRI or CT of the pituitary
Th: trans-sphenoidal microsurgery is the treatment of choice. Radiotherapy has a high incidence of hypopituitarims.
Medical management: bromocriptine (effective only in a minority of patients) and octreotide (a long-acting somatostatin analogue - very effective). It is administered as a s.c. injection three times daily.



Clinical features of acromegaly
type of  change             change                        manifestation
somatic                        acral changes             enlarged hands and feet
                                    musculoskeletal            arthralgias
                                    changes                        prognathism
                                                                        carpal tunnel syndrome
                                                                        proximal myopathy
                                    skin changes             sweating
                                    colon changes             polyps
                                                                        carcinoma
                                    cardiovascular            cardiomegaly
                                                                        hypertension
                                    visceromegaly            tongue
                                                                        thyroid
                                                                        liver
endocrine                        reproduction                        menstrual abnormalities
                                    problems                        galactorrhea
                                                                        decreased libido
                                    carbohydrate             impaired glucose tolerance
                                    metabolism                        diabetes mellitus
                                    lipid metabolism            hypertriglyceridemia

Gonadotropin-Secreting Pituitary Tumours
Mainly in males, are rare. Secrete usually FSH only.
Clin: 
·     signs of local pressure (visual impairment);
·     hypogonadism
Th: surgical removal ± subsequent radiotherapy

Thyrotropin-Secreting Pituitary Tumour
Extremely rare
Dg: increased TSH + increased T4
Th: surgery + radiotherapy
The Posterior Pituitary Gland
ADH is a 1084-dalton nonapeptide. It binds to receptors on the renal tubule, increasing the water permeability of the luminal membrane of the collecting duct epithelium, thus facilitating reabsorption of water. Maximal ADH effect results in a small volume of concentrated urine with osmolarity as high as 1200 mOsm/kg. Deficiency of ADH results in a large volume of very dilute urine (as low as 100 mOsm/kg).
ADH also binds to peripheral arteriolar receptors, causing vasoconstriction and increase in blood pressure; however, it also causes bradycardia and inhibition of sympathetic nerve activity.
Deficiency of ADH or insensitivity of the kidney to ADH ®  diabetes insipidus manifested as polyuria and polydipsia. Inappropriate secretion of ADH ®  the syndrome of inappropriate ADH secretion (SIADH) ® a hyponatremic state.
Oxytocin is a 1007-dalton nonapeptide that causes uterine smooth muscle contraction.  It is released by nipple stimulation and facilitates milk ejection by causing mammary duct myoepithelial cell contraction in response to nipple stimulation.

Diabetes Insipidus
Central (neurogenic) or renal (nephrogenic).
Patients are polyuric, secreting large volumes of diluted urine     dehydration  ®  thirst  ®  polydipsia.

Causes of Diabetes Insipidus
Causes of Central Diabetes Insipidus
·     idiopathic
·     familial
·     hypophysectomy
·     infiltration of hypothalamus and posterior pituitary
·     Langerhans cell histiocytosis
·     granulomas
·     infection
·     tumors
·     autoimmune

Causes of nephrogenic diabetes insipidus
·     idiopathic
·     familial
·     chronic renal disease (pyelonephritis, polycystosis)
·     hypokalemia
·     hypercalcemia
·     sickle cell anemia
·     drugs
            lithium
            fluoride
            demeclocycline
            colchicine

DD: primary polydipsia ® decreased ADH secretion ®  water diuresis. Random simultaneous samples of plasma and urine for sodium and osmolarity:  in diabetes insipidus, urine osmolarity < plasma osmolarity. Plasma osmolarity may be elevated, depending on the patient's state of hydration. In primary polydipsia, both plasma and urine are dilute.
The water deprivation test: the patient is denied fluids for 12 to 18 hours, and body weight, blood pressure, urine volume, urine specific gravity, and plasma and urine osmolarity are measured every 2 hours. If the body weight falls more than 3%, the study should be terminated.  A normal response is a decrease in urine output to 0.5 ml/min, as well as an increase in urine concentration to greater than that of plasma. Patients with DI maintain a high urine output, which continues to be dilute (specific gravity < 1.005 {200 mOsm/kg of water}). Patients with primary polydipsia increase their urine osmolarity to values > plasma osmolarity. Water deprivation is continued until the urine osmolarity plateaus (an hourly increase of < 30 mOsm/kg for three successive hours). At that point, 5 µg of  vasopressin is administered s.c., and the urine osmolarity is measured after 1 hour. Patients with complete central DI increase urine osmolarity above plasma osmolarity, whereas in nephrogenic DI the urine osmolarity increases less than 50%. Patients with primary polydipsia have increases < 10%.
Th: central DI - desmopressin acetate (DDAVP), a synthetic analog of ADH, is administered intranasally. Adequacy of replacement is monitored by serum osmolarity and sodium.
Nephrogenic DI
As far as possible, the underlying disease process should be reversed.  Diuretics with dietary salt restriction can be used.

SIADH
Plasma ADH concentrations are inappropriately high for plasma osmolarity, resulting in water retention leading to hyponatremia and decreased plasma osmolarity (< 280 mOsm/kg). Urine osmolarity is higher than the plasma osmolarity.

Disorders Associated with SIADH
type of disorder                                    disorder
pulmonary disorders                        malignant (oat cell carcinoma)
                                                            benign (TBC, pneumonia, abscess)
CNS disorders                                    meningitis
                                                            brain abscess
                                                            head trauma
adverse drug effects                        clofibrate
                                                            chlorpropamide
                                                            cyclophosphamide
                                                            phenothiazine
                                                            carbamazepine
tumours (ectopic                                    lymphoma
production of ADH)                        sarcoma
                                                            carcinoma of pancreas or duodenum

Th: the underlying condition should be treated. Fluid restriction is the cornerstone of treatment.

--------------